Simvastatin-loaded polymeric micelles are more effective and less toxic than conventional statins in a pre-clinical model of advanced chronic liver disease

Nanomedicine. 2020 Oct:29:102267. doi: 10.1016/j.nano.2020.102267. Epub 2020 Jul 15.

Abstract

Chronic liver disease (CLD) has no effective treatments apart from reducing its complications. Simvastatin has been tested as vasoprotective drug in experimental models of CLD showing promising results, but also limiting adverse effects. Two types of Pluronic® carriers loading simvastatin (PM108-simv and PM127-simv) as a drug delivery system were developed to avoid these toxicities while increasing the therapeutic window of simvastatin. PM127-simv showed the highest rates of cell internalization in rat liver sinusoidal endothelial cells (LSECs) and significantly lower toxicity than free simvastatin, improving cell phenotype. The in vivo biodistribution was mainly hepatic with 50% of the injected PM found in the liver. Remarkably, after one week of administration in a model of CLD, PM127-simv demonstrated superior effect than free simvastatin in reducing portal hypertension. Moreover, no signs of toxicity of PM127-simv were detected. Our results indicate that simvastatin targeted delivery to LSEC is a promising therapeutic approach for CLD.

Keywords: Cirrhosis; Drug delivery; Nanoparticles; Statins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Endothelial Cells / drug effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Liver / drug effects*
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology
  • Micelles
  • Polymers / chemistry
  • Polymers / pharmacology
  • Rats
  • Simvastatin / chemistry
  • Simvastatin / pharmacology*
  • Tissue Distribution / drug effects

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Micelles
  • Polymers
  • Simvastatin